Department of Nutrition, University of California, Davis, California.
Western Human Nutrition Research Center, Agricultural Research Service, USDA-ARS, Davis, California.
Immun Inflamm Dis. 2017 Dec;5(4):526-540. doi: 10.1002/iid3.162. Epub 2017 Aug 4.
Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)-induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.
We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.
TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.
Together, these results suggest that constitutively active TLR4-induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.
慢性低度炎症与肥胖和糖尿病有关。然而，代谢紊乱中导致和介导慢性炎症的原因尚不清楚。Toll 样受体 4（TLR4）通过分别识别病原体相关分子模式和内源性分子来介导感染诱导的和无菌性炎症。饱和脂肪酸可以激活 TLR4，而 TLR4 缺陷小鼠则可以防止高脂肪饮食（HFD）诱导的肥胖和胰岛素抵抗，这表明 TLR4 介导的炎症可能导致代谢功能障碍，如肥胖和胰岛素抵抗。
我们生成了两种在脂肪组织中表达组成型激活 TLR4 的转基因（TG）小鼠系，并确定这些 TG 小鼠是否会表现出增加的胰岛素抵抗。
与野生型对照相比，TG 小鼠在高脂肪或正常饲料喂养时并未表现出增加的胰岛素抵抗，尽管白色脂肪组织中局部炎症增加。此外，与野生型同窝仔相比，一条 TG 线的雌性在正常饲料喂养时表现出胰岛素敏感性提高，同时减少了肥胖和体重。无论基因型和饮食如何，雌性和雄性小鼠在代谢生物标志物和促炎基因以及 TLR4 信号转导的负调节剂的 mRNA 表达方面存在显著差异。
综上所述，这些结果表明，白色脂肪组织中组成型激活的 TLR4 诱导的炎症不足以诱导全身胰岛素抵抗，而高脂肪饮食诱导的胰岛素抵抗可能除了 TLR4 介导的炎症之外还需要其他信号。
